title: Assessment of the subchronic oral toxicity of d-limonene in dogs.
abstract: Several hydrocarbons, including d-limonene, have been shown to produce a male-rat-specific nephrotoxicity that is manifested acutely as exacerbation of hyaline droplet formation. In a study to assess the presence or absence of this response in a non-rodent species, the dog was selected as a relevant model because of an earlier report suggesting that d-limonene may be nephrotoxic in this species. Five male and five female adult beagle dogs per treatment group were gavaged twice daily over a 6-month period with tap-water (control) or d-limonene at 0.12 or 1.2 ml/kg body weight/day (100 or 1000 mg/kg body weight/day). The highest daily dose was determined in a pilot study to be close to the maximum tolerated dose for emesis (ED50 1.6 ml/kg body weight). The test compound was administered in divided doses to minimize the incidence of emesis. Feed consumption and body weight were unaffected by treatment. Linear regression analyses indicated a positive dose-related trend for absolute and relative female kidney weight and relative male kidney weight. There were no histopathological changes in the kidneys, evaluated by both haematoxylin and eosin and Mallory-Heidenhain staining, that could be associated with the organ-weight changes. Furthermore, there was no evidence of hyaline droplet accumulation nor of any other sign of hydrocarbon-induced nephropathy typical of those seen in male rats treated with d-limonene. Thus, dogs are refractory to the hyaline droplet nephropathy observed in male rats, thereby providing additional evidence that the male rat kidney is uniquely sensitive to hydrocarbons like d-limonene, and that this specific male rat nephropathic response may be inappropriate for interspecies extrapolation and human risk assessment.
authors.affiliation: Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45239.
authors.forename: D R
authors.initials: DR
authors.lastname: Webb
authors.forename: R L
authors.initials: RL
authors.lastname: Kanerva
authors.forename: D K
authors.initials: DK
authors.lastname: Hysell
authors.forename: C L
authors.initials: CL
authors.lastname: Alden
authors.forename: L D
authors.initials: LD
authors.lastname: Lehman-McKeeman
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D053138:Cyclohexenes; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000187:drug effects*; D000077222:Limonene; D008099:Liver / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D012044:Regression Analysis; D013729:Terpenes / Q000008:administration & dosage / Q000633:toxicity*; D014839:Vomiting / Q000139:chemically induced
chemical_list: D053138:Cyclohexenes; D013729:Terpenes; D002784:Cholesterol; D000077222:Limonene; D000469:Alkaline Phosphatase